Risperidone of the formula I is known to be prepared by the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2,-a]pyrimidin-4-one of the formula IIA: with 4-(2,4-difluorobenzoyl) piperidine of the formula III: in organic solvent such as methylene dichloride, acetonitrile, N,N-dimethyl formamide (DMF) or N-methyl pyrrolidone in the presence of an inorganic base such as sodium hydroxide, carbonate or bicarbonate at 50-100° C., followed by oximation and cyclisation (Spanish Patent No 2,050,069).
Inorganic bases used in the above reaction being sparingly to soluble in organic solvent used as medium for the reaction, they may not neutralise the acid by-product fast with the result that the neutralisation may be sluggish. Due to the slow removal of the acid by-product from the reaction mixture there are chances of decomposition of the condensation product thereby reducing the yield and purity thereof. The yield of condensation product obtained by this condensation process is low of the order of 63.1%. This process is therefore inefficient and uneconomical. The medium for the condensation being organic, isolation of the condensation product is to be carried out by quenching the reaction mixture with water followed by extraction with organic solvent such as methylene dichloride. Solvent extraction is cumbersome, lengthy and time-consuming and also engenders poor recovery of organic solvent used for the reaction. Also organic solvents such as DMF are reported to decompose in the presence of inorganic bases at elevated temperatures (Encyclopedia of Chemical,Technology, 3rd edition, 11, 263) further complicating isolation. Besides, use of organic solvents as medium for the reaction makes die process further expensive and uneconomical. Moreover, solvents such as DMF are hazardous and pollute environment when used in large scale and also entail effluent disposal/treatment problems.
Risperidone of Me formula I may also be prepared by the condensation of chlorotetrahydro pyridopyrimidine of the formula IIA with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole of the formula IV: in an organic solvent such as DMF, 4-methyl-2-pentanone, benzene, ethanol, 1,4-dioxane, tetrahydrofuran, nitrobenzene or 1-methyl-2-pyrrolidinone in the presence of an organic base such as N,N-diethylethanamine, 4-ethyl morpholine or N-(1-methylethyl)-2-propanamine or an inorganic base such as sodium or potassium carbonate, sodium hydrogen carbonate or sodium methoxide, hydroxide or hydride, usually at 85-90° C. (U.S. Pat. No. 4,804,663). The organic bases which may be used in the above condensation are expensive and their use makes the above reaction uneconomical. Inorganic bases when used in organic solvent medium may result in decomposed condensation product as earlier discussed. The yield of the product obtained by this method is low of the order of 46% and renders the process inefficient and uneconomical. The reaction medium being organic, the isolation of the condensation product is to be carried out by quenching the reaction mixture with water followed by filtration of the resulting solid and recrystallsation thereof from an organic solvent such as DMF. This isolation procedure besides being cumbersome, suffers from poor solvent recovery. Also due to use of inorganic bases in organic solvent such as DMF, isolation becomes further complicated for reasons as explained earlier. Organic solvents used as reaction medium further makes the process expensive and uneconomical. Also this process is not free from the disadvantages due to use of solvents such as DMF as aforesaid.
The intermediate chloro tetrahydro pyridopyrimidine of the formula IIA in the synthesis of anti-psychotic risperidone of the formula I may be obtained by hydrogenation of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2,-a]pyrimidin-4-one of the formula VA: in acetic acid medium at 50 psi and at 25-30° C. in the presence of Pd/C catalyst. (A Thesis entitled “Synthesis of Drugs & Drug Intermediates” submitted to “The University Of Mumbai” by Ms Evelyn D Lobo, p35, June 1996, for the degree of M Pharm Sci.). This hydrogenation may produce predominantly dechlorinated compounds as by-products, since dechlorination may be accelerated in acetic acid medium. This may result in low yield and purity of the product. The yield of the product obtained by this method is low of the order of 77%, thus making this process inefficient and uneconomical. The isolation of the product involves filtration of the catalyst followed by evaporation of acetic acid from the reaction mixture, dissolving the resulting residue in a solvent, deacidification and evaporation of solvent followed by recrystallisation of the resulting solid from 2-propanol. Such mutiple steps for isolation are cumbersome, lengthy and time consuming. Acetic acid is a hazardous and flammable solvent and pollutes the environment when used in large scale. Also its use makes the process expensive and further uneconomical.
The chloro tetrahydro pyridopyrimidine reactant of the formula IIA may also be prepared by hydrogenation of the 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2,-a]pyrimidin-4-one of the formula VI: using Pd/C catalyst in aqueous ethanol at 25-30° C. followed by reacting the resulting hydroxyethyl tetrahydro pyridopyrimidine compound of the formula VII: with thionyl chloride in methylene chloride at 25-30° C. for 24 hours (Spanish Patent No 2,050,069). This route involves two steps for the preparation of the compound of the formula IIA and is lengthy and time-consuming. Moreover, thionyl chloride is hazardous and when used in large scale, pollutes the environment. The overall yield of the product obtained by this method is low of the order of 44% due to two moderately yielding steps, thus making the process inefficient and uneconomical.
An object of the invention is to provide a process for the preparation of risperidone of the formula I, which is simple and less time consuming.
Another object of the invention is to provide a process for the preparation of risperidone of the formula I, which is inexpensive and economical.
Another object of the invention is to provide a process for the preparation of risperidone of the formula I, which results in high yield and purity of risperidone and is efficient.
Another object of the invention is to provide a process for the preparation of risperidone of the formula I, which is safe and does not pollute the environment.
Another object of the invention is to provide a process for the preparation of risperidone of the formula I, which is commercially feasible.
Another object of the invention is to provide a process for the preparation of tetrahydro pyridopyrimidine of the formula IIB, which is simple and less time consuming.
Another object of the invention is to provide a process for the preparation of tetrahydro pyridopyrimidine of the formula IIB, which is inexpensive and economical.
Another object of the invention is to provide a process for the preparation of tetrahydro pyridopyrimidine of the formula IIB, which results in high yield and purity of tetrahydro pyridopyrimidine and is efficient.
Another object of the invention is to provide a process for the preparation of chlorotetrahydro pyridopyrimidine of the formula IIB, which is safe and does not pollute the environment.
Another object of the invention is to provide a process for the preparation of chlorotetrahydro pyridopyrimidine of the formula IIB, which is commercially feasible.